The cell surface CD40 molecule is a member of the tumor necrosis factor receptor superfamily (TNFR) and a key regulator in both innate and adaptive immune responses. CD40 is expressed on human antigen presenting cells, in particular B cells, dendritic cells and macrophages, as well as on fibroblasts, smooth muscle cells, endothelial cells and epithelial cells. CD40 is also expressed on a wide range of tumor cells including all B-lymphomas, 30-70% of solid tumors, melanomas and carcinomas.
The natural ligand of CD40, designated CD154 or CD40L, is mainly expressed on activated T lymphocytes and platelets. The interaction of CD40 with CD40L on T cells induces both humoral and cell-mediated immune responses. CD40 regulates this ligand-receptor pair to activate B cells and other antigen-presenting cells (APC) including dendritic cells (DCs), driving T cell activation. For example, activation of CD40 on B cells induces B cell proliferation, somatic hypermutation, differentiation into antibody secreting cells and isotype switching in germinal centers of secondary lymphoid organs. In vitro studies have shown direct effects of CD40 activation on cytokine production (e.g. IL-6, IL-10, IL-12, TNF-α), expression of adhesion molecules and costimulatory receptors (e.g. ICAM, CD23, CD80 and CD86), and increased expression of MHC class I, MHC class II, and TAP transporter by B lymphocytes.
CD40 antibodies may elicit their antitumor effects by various mechanisms, including activation of antigen-presenting cells resulting in increased activity of tumor specific cytotoxic T lymphocytes and natural killer cells (NK cells), or direct antibody-mediated tumor cell apoptosis or cellular cytotoxicity of CD40 positive tumors. Systemic administration of anti-CD40 antibodies has however also been associated with adverse side effects, such as a cytokine release syndrome.
Thus, there is a need for improved anti-CD40 antibodies for cancer therapy and enhancement of immune response.